Combination drug therapy has been gaining a lot of importance in recent times. The reasons could be—avoidance of taking multiple tablets/capsules per day, savings on co-payment for different medicines and assurance of patient compliance to drug therapies. It is important to show that different drugs combined in the same dosage form should be stable during manufacture and storage and should not interact physically or chemically with each other or with excipients to produce degradation products. Each drug in the combination dosage form should show the desired release rate from the dosage form to get absorbed in sufficient quantities upon oral administration or release the drug to surrounding environment in case of other delivery routes.
Pharmaceutical capsule dosage forms are widely used in delivering drugs. The main two types of capsules are—hard shell capsules and soft shell capsules. The present patent relates to hard shell capsules. The capsules are normally prepared using gelatin and normally termed as hard gel capsules. In recent times, several polymers have been employed to manufacture hard shell capsules. In 1977, Christen and Cheng patented (U.S. Pat. No. 4,026,986) hard shell capsules manufactured using hydroxyalkyl starch. WO 1997004755 (International application #: PCT/EP1996/003263) prepared hard gelatin capsules with internal or external polymer coating using the double dipping technique. The inventors used polyvinyl alcohol and polyvinyl acetate polymers along with necessary additives.
Gennadios invented non-gelatin capsules (U.S. Pat. No. 6,214,376) comprising k-carrageenan, water-soluble plasticizer, and dextrins. The composition also included hydrolyzed starch as a variation. U.S. Pat. No. 6,517,865 claimed hard and soft capsules comprising of water-soluble cellulose ethers, hydrocolloids and sequestering agents. The capsules also comprised of a coating with polymers including cellulose acetate phthalate, hydromellose phthalate etc. In 2004 patent by Chen et al. (U.S. Pat. No. 6,752,953), authors described the usage of other polymers such as cellulose derivatives including cellulose, cellulose ester, methyl cellulose, hydroxypropyl methyl cellulose etc., acrylates including polyacrylate, polymethylacrylate, poly (methacrylate-methylmethacrylate) etc., and polyolefins including polyethylene, polypropylene, polyvinyl chloride, polyvinyl alcohol etc. to prepare capsules.
US patent application #2005/0142186 used low-substituted cellulose ether to produce hard capsules. The inventors also proposed a method for capsule preparation. The pins were dipped in the alkaline solution of low-substituted cellulose ether followed by dipping in an aqueous acid solution to form a gel (low-substituted cellulose ethers are soluble in alkaline medium and forms a gel in the acidic environment). The pins covered with the gel are further washed with water before the drying step. U.S. Pat. No. 6,949,256 used a mixture of kappa carrageenan and iota carrageenan. Kappa carrageenan is known to form a strong gel in the presence of potassium cations. However, these tend to be brittle and exhibit syneresis (exudating of liquid portion of the gel). Iota carrageenan tends to react with calcium cations and forms a weaker and more flexible gel.
A US patent application #2008/0,248,102 by Rajewski and Haslam prepared hard shell capsules with pullulan, a plasticizer and a dissolution-enhancing agent. The capsules were meant to dissolve in the mouth cavity (orally dissolving capsules). US patent application #2008/0,274,187 prepared hard capsule compositions comprising carrageenan, locust bean gum, xanthan gum, sorbitol, and pullulan. These capsules eliminated the problem of cracking, embrittlement, chipping and deformation due to water loss and mechanical stress. US patent application #2010/0,168,410 described a composition of hard capsules of hydroxypropyl methyl cellulose and the process of dip-coating manufacture. The dipping pins were heated at 55-95° C. and the polymer solution was maintained at 1 to 10° C. below its gelling temperature.
McConville et al. (Eur. J. Pharmaceutics & Biopharm. 57: 541-549 (2004) prepared a capsule filled with low-substituted hydroxypropyl cellulose on which a propranolol tablet was placed followed by an erodible tablet containing HPMC and lactose manufactured by either direct and wet granulation technique. The body of the capsule was precoated with insoluble ethyl cellulose suggesting the drug release only after the dissolution of the cap of the capsule. In this case, the capsule shell was not loaded with the drug—propranolol.
In the US patent application #2004/0,146,559, a film forming shell was formed on the inside core containing the active ingredient. The shell may have different properties to alter the drug release rates. In this patent, the core and the shell were manufactured in situ. In the present invention, the empty hard capsule shell containing the drug is produced by the manufacturer of capsules (such as Capsugel, Universal capsules, and Shionogi capsules).
In the U.S. Pat. No. 6,709,427, microsphere preparation was the core technology in which the microspheres were encapsulated to produce microcapsules. This is a totally different kind of drug delivery technique compared to the present patent application using empty, hard capsule shell in which the drug granules or powder are filled in the capsule shell body.
In the US patent application #2003/0,104,062, the capsules core is loaded with the drug. The shell surrounding the drug-containing core governed the release rate (zero order) of the drug by diffusion mechanism due to its swelling. The shell also promoted gastric retention of the capsules by swelling upon the imbibation of gastric fluid to a size that is retained in the stomach during the fed mode. In one embodiment, no drug was incorporated in the capsule shell composition. In another embodiment, the drug was incorporated in the shell to produce a burst effect. In this case, the same drug was incorporated in the core and in the shell/casing. In this patent, the preparation of capsule shell was part of the manufacturing process in situ. The desired zero order release and the manufacturing process are the two key differences between US patent application #2003/0104062 and the current patent application.
The subject of polymeric prodrugs has been studied widely. A review article (Joshi, H., Pharm. Tech., 12: 118, 120, 122, 124, 126, 128 and 130, (1988)) has summarized different types of polymeric drug delivery systems. U.S. Pat. No. 7,056,500 provided details developing a hydrolytically stable linkage between an opioid antagonist and poly (ethylene glycol). Choe and Greenwald described a method of making and using thiol-linked polymeric prodrugs (U.S. Pat. Nos. 7,262,164). 7,666,398 demonstrated the usage of polyanhydrides as a polymer backbone to prepare polymeric prodrugs. The low molecular weight drugs used with this method included one carboxylic acid group and at least one amine, thiol, alcohol or phenol group within its structure.
There are mainly two methods to prepare empty hard shell capsules: pin dip-coating and heat-melting. A liquid mass is produced by dissolving the capsule compositions in a solvent system or by melting at an appropriate temperature. In the pin dip-method, a plurality of pins maintained at a certain temperature dip in the solution and is withdrawn at a pre-determined rate while spinning. The pins coated with capsule composition are then dried at a gradual rate at a suitable temperature. The body and cap of the capsules are separated from the pins and then trimmed to an exact length. The method has been employed to prepare the body and cap of the capsules. The body and cap are joined together and a logo is printed, if necessary.
InnerCap, a UK-based company proposed combination capsules in which a capsule may contain another small capsule or a tablet along with granules. The granules may be made up of beads or other forms, which may contain more than one type of drug molecules. This way, more than one type of drug may be combined in the same capsule. However, all the drugs reside in the capsule core and there is no drug in the capsule shell composition.